Eosinophilic esophagitis is an increasingly recognized inflammatory condition of the esophagus whose economic burden is substantial. Prevention and treatment of the disease has been difficult due to lack of understanding about EoE etiology. We have found that family history is a risk for EoE with a significantly increased risk of EoE extending out to distant relatives, establishing a genetic contribution to EoE. We hypothesize that EoE predisposition genetic variants and tissue-based immune signatures are shared within high-risk EoE pedigrees defined as having a statistical excess number of EoE cases, and when studied in aggregate will further understanding of EoE etiology. We further postulate that genetic and histopathology differences will be observed in atopic compared to non-atopic EoE cases. We will use a resource unique to Utah to identify high-risk EoE pedigrees, a computerized genealogy for the state that has been record linked to electronic medical records. We will identify shared genetic regions among related EoE cases based on dense genotyping, and perform whole exome sequencing on selected distantly related EoE cases (e.g., second-cousins) to identify predisposition variants in targeted chromosomal regions. Use of the large pedigree study design is powerful and efficient for predisposition gene investigation as high-risk families are likely to be enriched for disease-causing variants and hence require only a small fraction of the sample size needed for a population-based design. Assessing differences in the underlying histologic immune milieu (i.e., mast cells, mast cell bound IgE, TSLP, IL33) within individuals and across family members may further characterize presentations of EoE; and, along with assessment of shared genetic and clinical characteristics, provides increased knowledge of disease pathogenesis. Relationships between genetic variants, histologic, and atopic/non-atopic comorbidities and presentations will be explored within individuals and families to determine whether genetic risk affects the histologic and/or clinical presentations of disease and whether histologic presentations influence the clinical appearances. Identification of predisposition genes for EoE will aid understanding of EoE etiology, as well as impact EoE screening, prevention, and treatment; and ultimately it has the potential to dramatically reduce disease morbidity.